29 | 04 | 2017

Borrelia miyamotoi disease

A pdf of a recent review may be accessed here.

 

History/m

Borrelia miyamotoi is related to the relapsing fever borreliae and was first described from Ixodes persulcatus ticks collected in Japan (Fukunaga et al., 1995). A relapsing fever-like borrelia was subsequently found in the North American tick, Ixodes scapularis (Scoles et al., 2001) and since then similar spirochaetes have been reported from over a wide geographical area in Eurasia and North America. At the time of writing these spirochaetes are all considered to be variants of B. miyamotoi.

Initially, the main significance of B. miyamotoi appeared to be that it is transmitted by the same tick species that are vectors of the Lyme borreliosis (LB) agent, B. burgdorferi sensu lato (s.l.), though with a markedly lower tick infection prevalence, but that unlike the LB borreliae, significant transovarial transmission occurs and also, similar to relapsing fever borrelias, B. miyamotoi can be observed in blood. Mistaken identity therefore almost certainly explains early reports of B. burgdorferi s.l. transovarial transmission in ticks and occurrence in blood smears from tick-exposed laboratory mice (Stanek et al., 1986), and also B. burgdorferi s.l.-infection prevalences in field-collected I. ricinus larvae as high as 21.0% (Rijpkema et al., 1994).

The first indication that B. miyamotoi may be pathogenic was a report in 2011 of an influenza-like illness in hospitalized Russian patients, who responded satisfactorily to treatment with ceftriaxone or doxycycline (Platonov et al., 2011). North American cases were first reported in 2013 and in one of these, an elderly and immunocompromised patient, the disease manifested as meningoencephalitis with spirochaetes demonstrable in the spinal fluid (Gugliotta et al., 2013). The first case in western Europe occurred in the Netherlands also manifesting as meningencephalitis in an immunocompromised patient and having demonstrable spirochaetes in the spinal fluid (Hovius et al., 2013). All of these cases resolved after treatment with antibiotics, i.e. doxycycline or ceftriaxone.

At present clinical disease resulting from infection with B. miyamotoi is considered to be very rare, though case rates may rise with increased awareness and improved diagnostic tests.

 

Clinical features

Most clinical cases have presented with fever a few weeks after the tick bite, and showed general symptoms such as mild fever, headache, fatigue and myalgia, though several American patients had concurrent LB or babesiosis infections, which may have complicated the presentation. In two cases in immunocompromised patients, one American (Gugliotta et al., 2013) and one European (Hovius et al., 2013), the infection manifested as meningoencephalitis. In the European patient slow cognitive processing, memory deficits and a disturbed gait developed slowly over a period of months. No fever occurred. His serum was weakly positive for B. burgdorferi s.l. but PCR analysis was negative. Nevertheless, because of multiple tick bites in the recent past, and because he had been using Rituximab – a B cell depletor that can interfere with antibody responses – the patient was treated for neuroborreliosis and the patient recovered. Strikingly, in a retrospective analysis motile spirochaetes were observed in pre-treatment spinal fluid and a positive PCR identified B. miyamotoi as the causative agent of the illness (Hovius et al., 2013). Considering that the organism is widespread in ticks in Europe, transmission to humans is probably not uncommon. However, most infections are probably only mildly symptomatic or asymptomatic, though some may occasionally lead to an acute febrile illness, and immunocompromised individuals can develop more severe symptoms. Thus, although there are some similarities with LB, B. miyamotoi-induced disease appears to be a distinct clinical entity.

 

Biology of the infectious agent

The original organism identified in Japan was designated B. miyamotoi sensu stricto and related organisms in America and Eurasia as B. miyamotoi sensu lato. So far this classification stands, though it is evident that distinct genotypes exist in these three geographical regions (Barbour et al., 2014).

The limited studies carried out on B. miyamotoi so far suggest that it can be transmitted both transstadially and transovarially, so that all tick stages are potential vectors. Nothing is known about where in the unfed infected tick the spirochaetes reside or about the transmission process. If B. miyamotoi resembles B. burgdorferi s.l. in its behaviour, a period of a day or two might be required after tick attachment to a host for the spirochaetes to translocate from the gut to the salivary glands and to upregulate surface proteins in anticipation of a vertebrate environment. If the pathogen occurs in the salivary glands of unfed ticks more rapid transmission might occur

The reservoir hosts of B. miyamotoi have yet to be definitively identified, but in Europe small rodents have been incriminated as reservoirs by xenodiagnosis (Burri et al., 2014).

 

Biology European vectors

The vectors of B. miyamotoi are thought to be I. ricinus in central and eastern Europe and I. persulcatus in parts of Eastern Europe and throughout temperate Asia, although this is based only on the occurrence of B. miyamotoi DNA in ticks and extrapolation from transmission studies in North America involving I. scapularis. The distribution of I. ricinus and I. persulcatus overlaps in the Baltic states and European Russia. Their non-parasitic (off-host) phases require a high humidity at the base of the vegetation (RH >85%) and ideal conditions are to be found in temperate deciduous woodland with patches of dense vegetation and little air movement, coupled with high humidity. The need for questing ticks to maintain a stable water balance is an important factor in determining the location and duration of activity. In general, activity will begin in spring and early summer, with ticks being found on vegetation and animals from late March. In habitats where desiccation is high, such as open areas, periods of activity will be shortened to only a few weeks – as opposed to several months in dense woodlands. In some areas a second, less intense, phase of questing activity occurs in the autumn.

The tick ambushes its host from the vegetation and attaches to the skin with specialized mouthparts for several days, the duration depending on the tick life cycle stage. Where I. ricinus is the vector, nymphs are most likely to cause human infections, since they are more numerous than adults both on the vegetation and from parasitised patients. In the case of I. persulcatus, adult females are the most likely vector stage, since the nymphs and larvae rarely bite humans.

For further details of the biology of Ixodes ricinus see the Lyme borreliosis page, Biology, tick.

 

Diagnosis

There is no pathognomonic symptom for infection with B. miyamotoi. Fever is probably a common feature in immunocompetent individuals, but was not present in two immunocompromised cases (Gugliotta et al., 2013; Hovius et al., 2013). Other reported nonspecific symptoms include headache, neck stiffness, fatigue, myalgias, arthralgias, abdominal pain, cough, and sore throat, and in cases of invasion of the central nervous system in cognitive and co-ordination dysfunction. Recurrent fever has been reported from 10% of American and Russian cases, but this feature is quite different from classic tick-borne relapsing fever, caused by several Borrelia spp. and transmitted by soft ticks. This infection is much more severe and is characterized by episodes of high fever followed by hypotension and diaphoresis (Telford et al., 2015).

Most cases of B. miyamotoi disease identified so far have been diagnosed with the use of molecular methods after failure to detect other tick-borne pathogens such as B. burgdorferi s.l. and Anaplasma phagocytophilum. In the absence of cultures of American and Eurasian strains of B. miyamotoi, some retrospective serological studies have been conducted with the GlpQ protein (an antigen that occurs in B. miyamotoi and is also expressed by other bacteria but is nonreactive to anti-B. burgdorferi s.l. antibody) (Krause et al., 2013). Although strains of B. miyamotoi in addition to the original Japanese HT31 can now be cultured (Margos et al., 2015; Wagemakers et al., 2014) no validated serological tests have yet been developed. However, variable major proteins have been identified as potential antigen targets (Wagemakers et al., 2016).

 

Treatment

The few cases that have been identified so far have responded favourably to 2-week courses of cephalosporin or doxycycline antibiotics.

 

Risk management

The same preventative measures against most other pathogens transmitted by ticks of the I. ricinus species complex apply i.e. wearing of appropriate protective clothing, application of repellents, examination of skin as soon as possible after potential tick exposure, prompt removal of attached ticks. The main significance of the infection may be in providing an alternative explanation for (acute) illness in cases initially presumed to be Lyme borreliosis or human granulocytic anaplasmosis, and diagnosing physicians should be aware of this possibility.

 

References

Barbour AG. 2014. Phylogeny of a relapsing fever Borrelia species transmitted by the hard tick Ixodes scapularis. Infect Genet Evol. S1567-1348(14)00157-9.

Burri C, Schumann O, Schumann C, Gern L. 2014. Are Apodemus spp. mice and Myodes glareolus reservoirs for Borrelia miyamotoi, Candidatus Neoehrlichia mikurensis, Rickettsia helvetica, R. monacensis and Anaplasma phagocytophilum? Ticks Tick Borne Dis. 5(3):245-51.

Fukunaga M, Takahashi Y, Tsuruta Y, Matsushita O, Ralph D, McClelland M, Nakao M. 1995. Genetic and phenotypic analysis of Borrelia miyamotoi sp. nov., isolated from the ixodid tick Ixodes persulcatus, the vector for Lyme disease in Japan. Int J Syst Bacteriol. 45(4):804-10.

Gugliotta JL, Goethert HK, Berardi VP, Telford SR 3rd. 2013. Meningoencephalitis from Borrelia miyamotoi in an immunocompromised patient. N Engl J Med. 368(3):240-5. doi: 10.1056/NEJMoa1209039.

Hovius JW, de Wever B, Sohne M, Brouwer MC, Coumou J, Wagemakers A, Oei A, Knol H, Narasimhan S, Hodiamont CJ, Jahfari S, Pals ST, Horlings HM, Fikrig E, Sprong H, van Oers MH. 2013. A case of meningoencephalitis by the relapsing fever spirochaete Borrelia miyamotoi in Europe. Lancet. 382(9892):658. doi: 10.1016/S0140-6736(13)61644-X.

Krause PJ, Narasimhan S, Wormser GP, Rollend L, Fikrig E, Lepore T, Barbour A, Fish D. 2013. Human Borrelia miyamotoi infection in the United States. N Engl J Med. 368(3):291-3. doi: 10.1056/NEJMc1215469.

Margos G, Stockmeier S, Hizo-Teufel C, Hepner S, Fish D, Dautel H, Sing A, Dzaferovic E, Rieger M, Jungnick S, Binder K, Straubinger RK, Fingerle V. Long-term in vitro cultivation of Borrelia miyamotoi. Ticks Tick Borne Dis. 2015 Mar;6(2):181-4.

Platonov AE, Karan LS, Kolyasnikova NM, Makhneva NA, Toporkova MG, Maleev VV, Fish D, Krause PJ. 2011. Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis.17(10):1816-23.

Rijpkema S, Nieuwenhuijs J, Franssen FF, Jongejan F. 1994. Infection rates of Borrelia burgdorferi in different instars of Ixodes ricinus ticks from the Dutch North Sea Island of Ameland. Exp Appl Acarol. 18(9):531-42.

Scoles GA, Papero M, Beati L, Fish D. 2001. A relapsing fever group spirochete transmitted by Ixodes scapularis ticks. Vector Borne Zoonotic Dis.1(1):21-34.

Stanek G, Burger I, Hirschl A, Wewalka G, Radda A. 1986. Borrelia transfer by ticks during their life cycle. Studies on laboratory animals. Zentralbl Bakteriol Mikrobiol Hyg A263(1-2):29-33.

Telford SR 3rd, Goethert HK, Molloy PJ, Berardi VP, Chowdri HR, Gugliotta JL, Lepore TJ. Borrelia miyamotoi disease: neither Lyme disease nor relapsing fever. Clin Lab Med. 2015 Dec;35(4):867-82. doi: 10.1016/j.cll.2015.08.002. Epub 2015 Sep 18. Review.

Wagemakers A, Oei A, Fikrig MM, Miellet WR, Hovius JW. The relapsing fever spirochete Borrelia miyamotoi is cultivable in a modified Kelly-Pettenkofer medium, and is resistant to human complement. Parasit Vectors. 2014 Sep 4;7:418. doi: 10.1186/1756-3305-7-418.

Wagemakers A, Koetsveld J, Narasimhan S, Wickel M, Deponte K, Bleijlevens B, Jahfari S, Sprong H, Karan LS, Sarksyan DS, van der Poll T, Bockenstedt LK, Bins AD, Platonov AE, Fikrig E, Hovius JW. Variable Major proteins as targets for specific antibodies against Borrelia miyamotoi. J Immunol. 2016 Apr 13. pii: 1600014. [Epub ahead of print]

 

 

Last Updated on Wednesday, 15 February 2017 20:42